This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. An important challenge in understanding intestinal immune responses in IBD remains achieving a clear understanding of the critical immunological balance between enforcing intestinal tolerance, while allowing for appropriate mucosal immune responses to pathogenic microbes. Mucosa resident antigen presenting cells, particularly dendritic cells and macrophages, hold great promise in this regard because they can uptake enteric bacteria and induce distinct types of immune responses, for example pro-inflammatory (Th1/Th17) versus regulatory (Treg/Tr1/Th3) T cells responses. However, lamina propria antigen presenting cell populations and their functions remain inadequately defined. Therefore, the overall objective of this project has been to gain a stronger fundamental understanding of how antigen presenting cells in the intestine function to modulate mucosal tolerance and immunity. We have continued to focus on the thorough investigation of the poorly characterized population of lamina propria macrophages and to compare them to mucosal DCs. The central hypothesis driving this research has been that the unique anti-inflammatory signature of intestinal lamina propria macrophages may promote the induction of regulatory T cells and mucosal tolerance. This hypothesis continues to be tested by analyzing the ability of lamina propria macrophages to modulate T cell responses in vitro and in vivo (Specific Aim 1), assessing their role in oral tolerance and intestinal inflammation (Specific Aim 2) and by comparing of overlapping and distinct qualities and functions of mucosal macrophages and DCs (Specific Aim 3). Information gained from these studies continues to represent major advancements in the understanding of intestinal antigen presenting cell functions as they relate to the induction of tolerogenic and immunogenic immune responses. This knowledge could ultimately aid in the rational design of immunotherapeutics to treat IBD.